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Clinical Features, Tumor Biology, and Prognosis Associated with MYC

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Clinical Features, Tumor Biology, and Prognosis Associated with MYC Modern Pathology (2015) 28, 1555–1573 © 2015 USCAP, Inc All rights reserved 0893-3952/15 $32.00 1555 Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP Zijun Y Xu-Monette1, Bouthaina S Dabaja2, Xiaoxiao Wang1, Meifeng Tu1, Ganiraju C Manyam3, Alexander Tzankov4, Yi Xia1, Li Zhang3, Ruifang Sun1, Carlo Visco5, Karen Dybkaer6, Lihui Yin1, April Chiu7, Attilio Orazi8, Youli Zu9, Govind Bhagat10, Kristy L Richards11, Eric D Hsi12, William WL Choi13, J Han van Krieken14, Jooryung Huh15, Maurilio Ponzoni16, Andrés JM Ferreri16, Michael B Møller17, Ben M Parsons18, Xiaoying Zhao19, Jane N Winter20, Miguel A Piris21, Timothy J McDonnell1, Roberto N Miranda1, Yong Li22, L Jeffrey Medeiros1 and Ken H Young1,23 1Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4University Hospital, Basel, Switzerland; 5San Bortolo Hospital, Vicenza, Italy; 6Aalborg University Hospital, Aalborg, Denmark; 7Memorial Sloan-Kettering Cancer Center, New York, NY, USA; 8Weill Medical College of Cornell University, New York, NY, USA; 9The Methodist Hospital, Houston, TX, USA; 10Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA; 11University of North Carolina School of Medicine, Chapel Hill, NC, USA; 12Cleveland Clinic, Cleveland, OH, USA; 13University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China; 14Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 15Asan Medical Center, Ulsan University College of Medicine, Seoul, South Korea; 16San Raffaele H Scientific Institute, Milan, Italy; 17Odense University Hospital, Odense, Denmark; 18Gundersen Lutheran Health System, La Crosse, WI, USA; 19Zhejiang University School of Medicine, Second University Hospital, Hangzhou, China; 20Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; 21Hospital Universitario Marqués de Valdecilla, Santander, Spain; 22Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA and 23The University of Texas School of Medicine, Graduate School of Biomedical Sciences, Houston, TX, USA MYC dysregulation, including MYC gene rearrangement and Myc protein overexpression, is of increasing clinical importance in diffuse large B-cell lymphoma (DLBCL). However, the roles of MYC and the relative importance of rearrangement vs overexpression remain to be refined. Gaining knowledge about the tumor biology associated with MYC dysregulation is important to understand the roles of MYC and MYC-associated biology in lymphomagenesis. In this study, we determined MYC rearrangement status (n = 344) and Myc expression (n = 535) in a well-characterized DLBCL cohort, individually assessed the clinical and pathobiological features of patients with MYC rearrangement and Myc protein overexpression, and analyzed the prognosis and gene expression profiling signatures associated with these MYC abnormalities in germinal center B-cell-like and activated B-cell-like DLBCL. Our results showed that the prognostic importance of MYC rearrangement vs Myc overexpression is significantly different in germinal center B-cell-like vs activated B-cell-like DLBCL. In germinal center B-cell-like DLBCL, MYC-rearranged germinal center B-cell-like DLBCL patients with Myc overexpression significantly contributed to the clinical, biological, and prognostic characteristics of the overall Correspondence: Dr KH Young, MD, Department of Hematopathology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. E-mail: [email protected] Received 10 July 2015; revised 16 August 2015; accepted 29 August 2015; published online 6 November 2015 www.modernpathology.org MYC-associated biology and prognosis in DLBCL 1556 ZY Xu-Monette et al Myc-overexpressing germinal center B-cell-like DLBCL group. In contrast, in activated B-cell-like DLBCL, the occurrence, clinical and biological features, and prognosis of Myc overexpression were independent of MYC rearrangement. High Myc levels and Myc-independent mechanisms, either tumor cell intrinsic or related to tumor microenvironment, conferred significantly worse survival to MYC-rearranged germinal center B-cell-like DLBCL patients, even among MychighBcl-2high DLBCL patients. This study provides new insight into the tumor biology and prognostic effects associated with MYC dysregulation and suggest that detection of both MYC translocations and evaluation of Myc and Bcl-2 expression is necessary to predict the prognosis of DLBCL patients. Modern Pathology (2015) 28, 1555–1573; doi:10.1038/modpathol.2015.118; published online 6 November 2015 MYC is a proto-oncogene that encodes the Myc Possible molecular mechanisms underlying the protein, which is critical for cell proliferation, growth, inconsistent clinical results may include presence or metabolism, differentiation, apoptosis, and immune absence of other genetic abnormalities and onco- – responses. In mouse models, Myc inactivation induces genic pathways,29 31 as well as another aspect of sustained tumor regression via both tumor cell- Myc function: promoting apoptosis.32 Moreover, intrinsic and host-dependent mechanisms.1 The selec- researchers have recently reported findings that tive small-molecule bromodomain inhibitor JQ1 has a Myc is a universal amplifier of 10–15% in human potent antiproliferative effect that was associated with genome, suggesting that Myc function is nonspecific the effective downregulation of MYC and Myc target and that the consequences of MYC activities are genes2 rendering this agent to have great therapeutic affected by pre-existing molecular programs in the potential.3 tumor cells.33,34 Therefore, tumor biology associated The chromosomal rearrangement or translocation with MYC/Myc (designated MYC herein) abnormal- involving MYC and other genes (most commonly the ities may have important roles in the observed immunoglobulin heavy-chain gene (IGH) locus) adverse prognosis. leads to Myc overexpression and occurs in ~ 10% Taken together, both MYC gene rearrangement and of diffuse large B-cell lymphomas (DLBCLs).4–8 Myc protein overexpression have been correlated DLBCL is the most common type of non-Hodgkin's with significantly adverse prognosis in DLBCL. lymphoma, and among MYC-rearranged aggressive However, how much of these two biomarkers over- lymphomas, DLBCL is the entity that clinicians most lap and differ, how much their associated tumor commonly encounter.9,10 Several studies have biology affects the prognostic effects, and whether reported that MYC translocations independently the MYC functional role is molecular context- predicted significantly poor survival in DLBCL dependent are not very clear. In this study, we patients.11–16 However, other studies found incon- compared the occurrence and clinicopathologic sistent results17–19 or limitations of its prognostic features of patients stratified by MYC rearrangement significance.20,21 and Myc expression status, and analyzed the The clinical significance of Myc overexpression in differential prognosis and gene expression profiling DLBCL has also been the source of much attention associated with these MYC abnormalities in a well- characterized DLBCL cohort to assess the utility of and controversy. Several groups including ours have these two genetic and protein biomarkers and found that DLBCL with high Myc protein expression explore the prognostic determinants. This study is detected by immunohistochemistry had inferior – important for achieving the goal of precision medi- survival.5,13,22 24 Furthermore, the poor prognosis cine in DLBCL. associated with Myc overexpression was contributed by cases with Myc/Bcl-2 coexpression—‘double- positive lymphoma’ (DPL)—which account for 18– 44% of DLBCLs.13,20,23–26 However, one study Patients and methods showed that the prognostic value of double-positive lymphoma was lost in younger DLBCL patients with Patients poor prognosis.27 Inconsistent results have been The study cohort consisted of 539 R-CHOP-treated reported regarding whether the prognostic signifi- patients with de novo DLBCL from the International cance of Myc or Myc/Bcl2 protein expression DLBCL Rituximab-CHOP Consortium Program, depends on MYC or MYC/BCL2 gene rearrangement including 466 cases from the training set of a status or not.8,13,20 Other issues include whether previous study,24 and additional 73 cases with either Myc/Bcl2 immunohistochemistry is robust and Myc immunohistochemistry or MYC gene rearrange- reproducible,28 and that immunohistochemistry cut- ment status determined. The diagnostic criteria, off values have varied among different study review process, and eligibility and exclusion criteria groups,13,20,23–26 which may affect the specificity of have been described previously.35,36 The cell-of- this combined biomarker for poorer prognosis. origin classification as either the germinal center Modern Pathology (2015) 28, 1555–1573 MYC-associated biology and prognosis in DLBCL ZY Xu-Monette et al 1557 B-cell-like (GCB) or activated B-cell-like (ABC) Statistical Analysis subtype was determined using gene expression profiling and/or immunohistochemistry for CD10, The clinical and pathobiological features of DLBCL patients
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